Browsing by Author "Park, Chul-Kyu"

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    Targeting CYP2J to reduce paclitaxel-induced peripheral neuropathic pain.
    (Proc Natl Acad Sci U S A, 2016-11-01) Sisignano, Marco; Angioni, Carlo; Park, Chul-Kyu; Meyer Dos Santos, Sascha; Jordan, Holger; Kuzikov, Maria; Liu, Di; Zinn, Sebastian; Hohman, Stephan W; Schreiber, Yannick; Zimmer, Béla; Schmidt, Mike; Lu, Ruirui; Suo, Jing; Zhang, Dong-Dong; Schäfer, Stephan MG; Hofmann, Martine; Yekkirala, Ajay S; de Bruin, Natasja; Parnham, Michael J; Woolf, Clifford J; Ji, Ru-Rong; Scholich, Klaus; Geisslinger, Gerd
    Chemotherapy-induced peripheral neuropathic pain (CIPNP) is a severe dose- and therapy-limiting side effect of widely used cytostatics that is particularly difficult to treat. Here, we report increased expression of the cytochrome-P450-epoxygenase CYP2J6 and increased concentrations of its linoleic acid metabolite 9,10-EpOME (9,10-epoxy-12Z-octadecenoic acid) in dorsal root ganglia (DRGs) of paclitaxel-treated mice as a model of CIPNP. The lipid sensitizes TRPV1 ion channels in primary sensory neurons and causes increased frequency of spontaneous excitatory postsynaptic currents in spinal cord nociceptive neurons, increased CGRP release from sciatic nerves and DRGs, and a reduction in mechanical and thermal pain hypersensitivity. In a drug repurposing screen targeting CYP2J2, the human ortholog of murine CYP2J6, we identified telmisartan, a widely used angiotensin II receptor antagonist, as a potent inhibitor. In a translational approach, administration of telmisartan reduces EpOME concentrations in DRGs and in plasma and reverses mechanical hypersensitivity in paclitaxel-treated mice. We therefore suggest inhibition of CYP2J isoforms with telmisartan as a treatment option for paclitaxel-induced neuropathic pain.
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    β-arrestin-2 regulates NMDA receptor function in spinal lamina II neurons and duration of persistent pain.
    (Nat Commun, 2016-08-19) Chen, Gang; Xie, Rou-Gang; Gao, Yong-Jing; Xu, Zhen-Zhong; Zhao, Lin-Xia; Bang, Sangsu; Berta, Temugin; Park, Chul-Kyu; Lay, Mark; Chen, Wei; Ji, Ru-Rong
    Mechanisms of acute pain transition to chronic pain are not fully understood. Here we demonstrate an active role of β-arrestin 2 (Arrb2) in regulating spinal cord NMDA receptor (NMDAR) function and the duration of pain. Intrathecal injection of the mu-opioid receptor agonist [D-Ala(2), NMe-Phe(4), Gly-ol(5)]-enkephalin produces paradoxical behavioural responses: early-phase analgesia and late-phase mechanical allodynia which requires NMDAR; both phases are prolonged in Arrb2 knockout (KO) mice. Spinal administration of NMDA induces GluN2B-dependent mechanical allodynia, which is prolonged in Arrb2-KO mice and conditional KO mice lacking Arrb2 in presynaptic terminals expressing Nav1.8. Loss of Arrb2 also results in prolongation of inflammatory pain and neuropathic pain and enhancement of GluN2B-mediated NMDA currents in spinal lamina IIo not lamina I neurons. Finally, spinal over-expression of Arrb2 reverses chronic neuropathic pain after nerve injury. Thus, spinal Arrb2 may serve as an intracellular gate for acute to chronic pain transition via desensitization of NMDAR.